Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma
Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma
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人胶质母细胞瘤中 CYP46A1 缺失介导的胆固醇稳态改变的治疗意义
DOI：
10.15252/emmm.201910924
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发表时间：
2019-11-28
影响因子：
11.1
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
Han, Mingzhi;Wang, Shuai;Wang, Jian
胆固醇代谢失调是包括胶质母细胞瘤（GBM）在内的许多癌症的标志，但其在疾病进展中的作用尚不清楚。在这里，我们发现胆固醇24-羟化酶（CYP46A1）是GBM中最严重的胆固醇代谢失调基因之一，它是一种脑特异性酶，负责通过将胆固醇转化为24(S)-羟基胆固醇（24OHC）来消除胆固醇。与正常脑组织相比，GBM样品中CYP46A1显著降低。在人类胶质瘤中，CYP46A1表达的减少与肿瘤分级增加和预后不良相关。CYP46A1的异位表达通过增加24OHC水平抑制细胞增殖和体内肿瘤生长。RNA-seq显示，24OHC处理GBM细胞通过调节LXR和SREBP信号传导抑制肿瘤生长。Efavirenz是一种CYP46A1的激活剂，已知可以穿透血脑屏障，在体内抑制GBM的生长。我们的研究结果表明，CYP46A1是GBM中细胞胆固醇的关键调节因子，CYP46A1/ 24ohc轴是一个潜在的治疗靶点。
Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for the elimination of cholesterol through the conversion of cholesterol into 24(S)-hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. CYP46A1 was significantly decreased in GBM samples compared with normal brain tissue. A reduction in CYP46A1 expression was associated with increasing tumour grade and poor prognosis in human gliomas. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. RNA-seq revealed that treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz, an activator of CYP46A1 that is known to penetrate the blood-brain barrier, inhibited GBM growth in vivo. Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target.